Field of the Invention
This invention is directed to compounds, pharmaceutical compositions and methods. The methods of this invention are useful in treating a condition mediated at least in part by xanthine oxidase including by way of example, gout, hyperuricemia, hypoxia and the like.
State of the Art
Gout is caused by hyperuricemia, namely, abnormally high levels of uric acid in the blood. Gout is usually presented as acute inflammatory arthritis, as well as tophi, kidney stones, or urate nephropathy. Gout affects 1-2% of adults in developed countries and represents the most common case of inflammatory arthritis in men. In the United States, gouty arthritis accounts for millions of outpatient visits annually. Furthermore, gout and hyperuricemia are also associated with chronic diseases such as hypertension, diabetes mellitus, metabolic syndrome, and renal and cardiovascular disease.
Xanthine oxidase (XO) is a form of a molybdoflavin protein, xanthine oxidoreductase (XOR). It plays an important role in the catabolism of purines in humans, as it catalyzes the oxidation of hypoxanthine to xanthine and then catalyzes the oxidation of xanthine to uric acid. Meanwhile, reactive oxygen species (ROS), including superoxide and H2O2, are generated during this process. In a bioprotective role, uric acid can serve as an antioxidant to prevent macromolecular damage by ROS. However, overproduction of uric acid causes hyperuricemia which can lead to gout and other diseases or conditions. Therefore, maintaining uric acid at normal levels represents an important therapeutic goal for the prevention of gout and related disorders. For most patients with primary gout, the condition is directly related to the overproduction of uric acid (hyperuricemia).
Currently, two drugs have been developed to treat gout. Allopurinol is the most commonly used therapy for chronic gout and has been used clinically for more than 40 years. Allopurinol lowers uric acid production by inhibiting XO activity, and is used as a first-line urate-lowering phamacotherapy. Allopurinol, a structural isomer of hypoxanthine, is hydroxylated by XO to oxypurinol, which coordinates tightly to the reduced form of the molybdenum center, replacing the Mo—OH group of the native enzyme. Unfortunately, while rare, allopurinol has life-threatening side effects such as a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and renal toxicity, for which the mortality rate approaches 20%. It also causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TENS), two life-threatening dermatological conditions. Febuxostat, a non-purine xanthine oxidase inhibitor, has been approved for the management of gout in Europe and the United States. Side effects are also found with this drug including elevated serum liver enzymes, nausea, diarrhea, arthralgia, headache, and rash.
Notwithstanding the need for drugs with improved safety in the treatment of gout, hyperuricemia, and related disorders, drugs available for treatment and prevention of such disorders remain limited. Therefore, safe and effective xanthine oxidase inhibitors are needed for treating such disorders.